Allografting

Toxicity-reduced, myeloablative allograft followed by lenalidomide maintenance as salvage therapy for refractory/relapsed myeloma patients

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Abstract

Relapse after dose-reduced allograft in advanced myeloma patients remains high. To reduce the risk of relapse, we investigated a myeloablative toxicity-reduced allograft (aSCT) consisting of i.v. BU and CY followed by lenalidomide maintenance therapy in 33 patients with multiple myeloma (MM) who relapsed following an autograft after a median of 12 months. The cumulative incidence of non-relapse mortality at 1 year was 6% (95% confidence interval (CI): 0–14). After a median interval of 168 days following aSCT, 24 patients started with a median dose of 5 mg (r, 5–15) lenalidomide without dexamethasone. During follow-up, 13 patients discontinued lenalidomide owing to progressive disease (n=6), GvHD (n=3), thrombocytopenia (n=2), or fatigue (n=2). Major toxicities of lenalidomide were GvHD II–III (28%), viral reactivation (16%), thrombocytopenia (III–IV°,16%), neutropenia (III/IV°, 8%), peripheral neuropathy (I/II°, 16%), or other infectious complication (8%). Cumulative incidence of relapse at 3 years was 42% (95% CI: 18–66). The 3-year estimated probability of PFS and OS was 52% (95% CI: 28–76) and 79% (95% CI: 63–95), respectively. Toxicity-reduced myeloablative allograft followed by lenalidomide maintenance is feasible and effective in relapsed patients with MM, but the induction of GvHD should be considered.

Introduction

The introduction of reduced-intensity conditioning has broadened the use of allo-SCT in patients with multiple myeloma (MM), especially in patients with refractory disease and relapse after an autograft.1, 2, 3, 4, 5, 6, 7, 8 In comparison to standard myeloablative conditioning regimen, reduced-intensity conditioning regimen resulted in lower non-relapse mortality (NRM) but also in a higher risk of relapse.9 Retrospective studies suggest that the intensity of the conditioning regimen correlates with the risk of relapse.10 Despite the observation within the EBMT registry that NRM has significantly improved after standard myeloablative conditioning in the transplant period after 199411 no further trial of myeloablative conditioning followed by allo-SCT has been published in recent years. Likewise, in auto-SCT, maintenance therapy with novel agents has become an option to lower the risk of relapse.12, 13 Here, we report results of a myeloablative, toxicity-reduced conditioning regimen consisting of i.v. BU (11.2 mg/kg) and CY (120 mg/kg) followed by lenalidomide maintenance in 33 patients with MM with relapsed or refractory myeloma.

Patients and methods

Patients’ eligibility

Patients with MM and failure of a prior autograft or refractory disease with failure to yield autologous stem cells could be enrolled in this study. To be included, patients should be aged between 18 and 65 years and have sufficient cardiac function (ejection fraction >30%), a creatinine clearance >50 mL/min, a lung diffusion capacity of at least 50%, and liver enzyme value not more than 3 × upper the limit of normal. Patients and donors were typed for human leucocyte antigen (HLA)-A, B, C and DRB1 and DQB1 with sequence-specific oligonucleotype and 1 mismatch on allele or Ag level in class I or II was allowed. All patients gave written consent to the protocol. A total of 15 patients received lenalidomide within a prospective dose-finding protocol (NCT 00778752), and toxicity results have been reported elsewhere.24 Lenalidomide therapy was started only if there was no sign of infection or GVHD. The primary endpoint of the study was NRM at 1 year. Secondary objectives were evaluation of response, incidence of acute GVHD, progression, OS, and toxicity due to lenalidomide maintenance therapy.

Treatment plan

The treatment consists of BU 14 × 0.8 mg/kg (=11.2 mg/kg) by i.v. infusion from day –6 to – 4 and CY by i.v. infusion of 120 mg/kg (day –2 and day –1). One patient received BU 4.8 mg/kg i.v., total marrow irradiation (TMI) (9 Gy) and CY (120 mg/kg). To prevent GVHD antithymocyte globulin (ATG Fresenius, Gräfelfing, Germany) was given at a median dose of 20 mg/kg on day –3, –2, and –1 followed by allo-SCT on day 0. Stem cell source was PBSC in all patients and the median number of transplanted CD34+ cells/kg was 6.3 × 106/kg (range, 2.3 × 106 to 11.2 × 106/kg). G-CSF (5 μg/kg) was given intravenously from day +5 after allo-SCT and was continued until sustained neutrophil engraftment. Lenalidomide should be started at the earliest on day +120 after transplantation if no signs of infection or GVHD could be seen. One patient with stable disease (SD) and increasing M-protein without fulfilling the definition of progressive disease received lenalidomide already on day 78 post allografting. Lenalidomide was started at a median dose of 5 mg without dexamethasone for 21 days followed by a 1-week rest. Four cycles were planned but if no severe toxicities were observed, further lenalidomide cycles with increased doses were allowed according to tolerability and disease status.

Statistical considerations

Actuarial curves were estimated according to the Kaplan–Meier method, and the significance was estimated by the log-rank test. OS was measured from transplantation to death from any cause. Patients who were still alive at follow-up were censored at the last follow-up date. PFS was calculated from transplantation until relapse/progression or death from any cause. Patients who were still alive at the time of analysis were censored at the last follow-up date. NRM was determined from the date of transplantation until death related to transplantation. Patients who died from other causes were censored at the time of death. The cumulative incidence method was used to estimate the incidence of NRM and relapse to account for competing event. Calculations were performed in SPSS version 15.0 (SPSS, Chicago, IL, USA). The competing risk analyses were done with the ACCorD (V. Gebski, National Health and Medical Research Council, Clinical Trial Center, University of Sydney). The following factors were included in the univariate analysis: age, HLA match, gender, deletion 13q14, number of prior autografts, chemosensitivity prior transplantation, mismatch, interval between autologous and allo-SCT.

Patients’ characteristics

Patients’ characteristics are shown in detail in Table 1. A total of 33 patients were enrolled in the study between July 2006 and November 2010. One patient was 67 years of age at time of registration; however, this patient remained included in this analysis. One patient received total marrow irradiation (9 Gy), BU (4.8 mg/kg i.v.), and CY (120 mg/kg) due to extramedullary disease. The median age of the patients was 50 years (range 36-67). Patients’ gender was male 26 and female 7. Cytogenetic abnormalities on chromosome 13 detected by FISH was available in 29 patients: deletion 13q14 was seen in 13 patients. In three also t(4;14) and in two del 17p was found. Sixteen patients had received 1 previous autograft, 15 had 2 prior autografts and 1 patient had 3 prior autografts. One patient with disease refractory to two lines of induction therapy failed to yield autologous stem cells. The median time between last autograft and allo-SCT was 20 months (range 2–51). The median duration of remission after autograft was 12 months (r, 1–48). Six patients had extramedullary disease at time of registration and ten patients had received prior radiotherapy. Six patients were transplanted from an HLA-identical sibling and 19 patients were transplanted from fully 10/10 allele matched unrelated donor, 8 patients had a mismatched donor. Before allo-SCT, 1 patient achieved CR, 21 patients achieved PR and 3 patients had SD, while 3 patients had refractory disease and 5 patients were treated with allo-SCT without salvage treatment after relapsed to autologous transplantation (Table 1).

Table 1 Patient’s characteristics (n=33)

Supportive care

Prophylaxis of GvHD consisted of CsA (3 mg/kg) given from day –1 to day +180 after transplantation. The dose of CsA was adjusted to serum level of 200 to 250 μg/L. CsA was tapered from day +140 and discontinued at day +180, if no signs of GvHD were observed. If GvHD occurred during lenalidomide treatment, CsA was continued and if the dose was already reduced, CsA dose was adjusted again to serum level 200–250 μg/L. Mycophenolate mofetil 2 × 1000 mg/m2 was given from day +1 to day +28 after transplantation. All patients were nursed in a single room equipped with a HEPA filter. Antibiotic prophylaxis consisted of ciprofloxacin and antifungal prophylaxis either of fluconazol, or more recently of posaconazol. Aciclovir was given as herpes prophylaxis from day +1 until day +180. Scoring of acute GVHD was performed according to Przepiorka et al.14 Response to treatment was defined according to the European Group of Blood and Marrow Transplantation criteria.15 Briefly, CR required a disappearance of monoclonal gammopathy in serum and urine as determined by immunofixation analysis for at least 6 weeks and less than 5% plasma cells in BM aspirate. A PR was defined as >50% reduction and a minor response as >25% reduction on paraprotein level, respectively; no change was defined as <25% decrease or increase of the paraprotein. Relapse was defined as occurrence of the monoclonal protein or BM plasmacytosis in case of prior CR. Progression of non-CR patients required at least 25% increase of paraprotein and an absolute increase of serum and/or urine M-protein of 5 g/L in serum and/or 200 mg in 24 h urine specimen or development of new bone lesions or extramedullary plasmacytomas.

Results

Non-relapse mortality

Two patients died owing to therapy-related complications that were infectious complication (fungal infection) and multiorgan failure resulting in a cumulative incidence of NRM at 1 year of 6% (95% CI: 0–14%) (Figure 1a) No significant factor for increased NRM could be found in the univariate analysis.

Figure 1
figure1

Cumulative incidence of treatment related mortality (a) and of relapse (b).

Engraftment

The median time for leukocyte engraftment >1.0 × 109/L was 10 days (r, 8–15). The median time to platelet engraftment >20 × 109/L was 14 days (r, 9–86). No primary or secondary graft failure was observed (Table 3).

GVHD after transplantation

40% of the patients did not experience any acute GvHD. 25% experienced mild grade I acute GvHD and 28% grade II GvHD. Severe grade III GvHD was seen in 6% of the patients. The overall grade II-III GvHD was 34% (Table 3).

Toxicity of lenalidomide

The median interval between transplant and start of lenalidomide was 168 days (r, 78–425). The median starting dose was 5 mg (r, 5–15). Nine patients did not receive lenalidomide maintenance therapy because of ongoing GvHD, cytopenia or patient’s wishes. The median number of lenalidomide cycles was 6 (r, 1–30). The major toxicities of lenalidomide were acute GvHD grade II–III (28%), viral reactivation (16%), thrombocytopenia grade III/IV (16%), neutropenia grade III/IV (8%), peripheral neuropathy grade I–II (16%) or other infectious complications (8%) (Table 2). Only two patients who experienced GvHD after lenelidomide had also GvHD before lenalidomide treatment. During follow-up, 13 patients discontinued lenalidomide treatment owing to progressive disease (n=6), GvHD (n=3), thrombocytopenia (n=2) or fatigue (n=2). In ten patients, lenalidomide dose could be increased to 10 mg and 15 mg and in 1 patient to 25 mg.

Table 2 Lenalidomide toxicity

Response

Before lenalidomide was started, the remission status in those patients were CR: n=7 (29%), PR: n=13 (54%), SD: n=4 (17%). After lenalidomide treatment 7 patients with PR and 1 patient with SD converted to CR and 1 patient with SD converted to PR. Overall for all 30 response-evaluable patients, CR, PR and SD was noted in 46%, 48%(21% VGPR) and 3%, respectively. In 14 patients, lenalidomide was almost used in combination with dexamethasone as salvage therapy before allo-SCT and all but one responded also to lenalidomide post-allogeneic transplantation. The patient who did not respond prior transplantation did neither respond after allogeneic transplanatation.

Relapse

During follow-up, 9 patients experienced relapse resulting in a cumulative incidence of relapse at 3 years of 42% (95% CI: 18–66%). In six of the non-responding or progressing patients during lenalidomide therapy, four received donor lymphocyte infusion (median dose 5 × 106 CD3+ cells/kg) and two patients responded with PR or CR, respectively. (Table 3 and Figure 1b).

Table 3 Results

Survival

After a median follow-up of 19 months (r, 3–58) the 3-year estimated probability of PFS and overall-free survival was 52% (95% CI: 28–76%) and 79% (95% CI: 63–95%), respectively (Figure 2). The median PFS and the median OS were not reached so far. In univariate analysis for 3-year survival, no significant factor could be found.

Figure 2
figure2

Progression-free (a) and overall survival (b) after toxicity reduced allograft followed by lenalidomide maintenance.

Discussion

The use of allo-SCT either as front-line therapy or as salvage therapy in patients with MM remains controversial. Novel active drugs have improved the treatment options for myeloma patients.16, 17, 18, 19, 20 Salvage treatment with lenalidomide/dexamethasone for relapsed/refractory patients resulted in a median PFS and OS of about 11 and 22 months, respectively.16, 18 A recent prospective trial performed by the EBMT with melphalan-/fludarabine-based, dose-reduced conditioning and allograft from unrelated donors resulted in a similar median PFS and OS but the Kaplan–Meier curve suggests a plateau after 5 years at about 20%.8 A direct prospective comparison between allografting and conventional therapy is lacking so far.

In donor vs no-donor comparison, de Lavallade et al. could show in a small study that patients with an HLA-identical sibling who underwent dose-reduced allograft had a significantly better event-free survival than patients without an HLA-identical sibling.21 A concern of allogeneic SCT is the high incidence of relapse that exceeds 55% at 3 years in the EBMT trial using a reduced-intensity melphalan (140 mg/m2)/fludarabine regimen. To lower the risk of relapse, we used an intensified conditioning regimen followed by lenalidomide maintenance therapy. The use of i.v. BU has been shown to reduce risk of veno-occlusive disease and reduce treatment-related morbidity and mortality.22 Despite the use of unrelated and mismatched unrelated donors that has been shown in previous trials as major risk factor for non-relapse mortality at 1 year was only 6% in the current trial. And, despite the observed reduced treatment-related mortality for the transplants performed in the more recent years,11 one might have expected at least a mortality of at least 20% in this heavily pretreated group of patients, who all but one had received at least one prior autograft. Even in the prospective EBMT trial with similar inclusion criteria but using a melphalan-based reduced intensity regimen, the one year transplant-related mortality was 25%.8 Whereas the EBMT study was a multicentre trial, the current study was performed only in a single experienced centre that may explain the low mortality. Another reason might be the use of i.v. BU that has been shown in other trials to have a treatment-related mortality of less than 5%.23

Despite the existing graft-versus-myeloma effect, it has been hypothesized that for advanced myeloma patients effective cytoreductive regimens are also mandatory to achieve CR and long-term freedom from disease.10 A recent update of a small phase II study using myeloablative conditioning regimen (TMI, Bu, Cy) followed by HLA-identical sibling transplantation has reported a 50% survival at 12 year after a median follow-up of 105 months. Furthermore, those who achieved a CR have a relapse-free survival at 12 years of 60%.24

Another aim to improve the results in allografting of myeloma patients is the introduction of lenalidomide post transplant. Lenalidomide maintenance therapy that started at a median of 168 days after transplantation induces some toxicity that was mainly GVHD related. Twenty eight percent of the patients experienced grade II–III acute GVHD after lenalidomide, and a previous dose-finding study has shown an increase of natural killer cells cytotoxicity but also an early increase of IFN gamma secreting T cells.25 In a similar study by the HOVON group investigating 10 mg lenalidomide after allo-SCT for myeloma patients, 37% developed acute GVHD.27 Other toxicities were myelosuppression and fatigue, and according to the recently published dose-finding study, the starting dose should not exceed 5 mg. Nevertheless, owing to the described toxicity, about 50% of the patients had to discontinue the lenalidomide treatment periodically or permanently. Because lenalidomide was usually started while immunosuppressive agents were reduced, a major contribution of CsA dose reduction on the occurrence of GVHD cannot be excluded. The efficacy of lenalidomide is highlighted by the fact that seven patients with PR and one patients with SD after transplantation achieved CR after lenalidomide treatment. Even if the true value of lenalidomide post allograft can only be determined by a prospective randomised study, the relative long PFS of 52% at 3 years is higher than the reported 3-year PFS in similar allogeneic studies without lenalidomide.2, 3, 8, 9

In the current trial, neither del 13q14 or the use of mismatch donors could be identified as risk factor for survival. As data about t(4;14) or 17p were not available in all patients, a detailed cytogenetic impact could not be investigated. Interestingly, no impact on survival was seen for chemosensitivity to salvage therapy before allo-SCT. That is in contrast to the retrospective EBMT study9 but in accordance with data from the Seattle group26 and the prospective EBMT trial.8 However, given the low number of chemorefractory patients included in the current study, no firm conclusion can be drawn. Overall, this study shows that a more intensive myeloablative toxicity-reduced allograft is feasible in heavily pretreated patients with myeloma who already experienced relapse to an autograft. Furthermore, lenalidomide post allografting has acceptable toxicities and may have contributed to the encouraging overall and PFS but triggering of GVHD should be considered.

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Acknowledgements

NK received research funding from Celgene. MK and GS received honorarium from Celgene.

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Correspondence to N Kröger.

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The authors declare no conflict of interest.

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Kröger, N., Zabelina, T., Klyuchnikov, E. et al. Toxicity-reduced, myeloablative allograft followed by lenalidomide maintenance as salvage therapy for refractory/relapsed myeloma patients. Bone Marrow Transplant 48, 403–407 (2013) doi:10.1038/bmt.2012.142

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Keywords

  • myeloablative conditioning
  • allo-SCT
  • lenalidomide
  • auto-SCT
  • salvage therapy
  • multiple myeloma

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